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In vitro synergy and enhanced murine brain penetration of saquinavir coadministered with mefloquine.

Owen, A; Janneh, O; Hartkoorn, RC; Chandler, B; Bray, PG; Martin, P; Ward, SA; Hart, CA; Khoo, SH; Back, DJ (2005) In vitro synergy and enhanced murine brain penetration of saquinavir coadministered with mefloquine. Journal of Pharmacology and Experimental Therapeutics, 314 (3). 1202 - 1209 (8). ISSN 0022-3565 https://doi.org/10.1124/jpet.105.086272
SGUL Authors: Janneh, Omar

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Abstract

Highly active antiretroviral therapy has substantially improved prognosis in human immunodeficiency virus (HIV). However, the integration of proviral DNA, development of viral resistance, and lack of permeability of drugs into sanctuary sites (e.g., brain and lymphocyte) are major limitations to current regimens. Previous studies have indicated that the antimalarial drug chloroquine (CQ) has antiviral efficacy and a synergism with HIV protease inhibitors. We have screened a panel of antimalarial compounds for activity against HIV-1 in vitro. A limited efficacy was observed for CQ, mefloquine (MQ), and mepacrine (MC). However, marked synergy was observed between MQ and saquinavir (SQV), but not CQ in U937 cells. Furthermore, enhancement of the antiviral activity of SQV and four other protease inhibitors (PIs) by MQ was observed in MT4 cells, indicating a class specific rather than a drug-specific phenomenon. We demonstrate that these observations are a result of inhibition of multiple drug efflux proteins by MQ and that MQ also displaces SQV from orosomucoid in vitro. Finally, coadministration of MQ and SQV in CD-1 mice dramatically altered the tissue distribution of SQV, resulting in a >3-fold and >2-fold increase in the tissue/blood ratio for brain and testis, respectively. This pharmacological enhancement of in vitro antiviral activity of PIs by MQ now warrants further examination in vivo.

Item Type: Article
Keywords: Antimalarials, Brain, Drug Synergism, HIV Protease Inhibitors, HIV-1, Humans, Mefloquine, Membrane Transport Proteins, Multidrug Resistance-Associated Proteins, P-Glycoprotein, Protein Binding, RNA, Messenger, Saquinavir, U937 Cells
SGUL Research Institute / Research Centre: Academic Structure > Institute of Medical & Biomedical Education (IMBE)
Academic Structure > Institute of Medical & Biomedical Education (IMBE) > Centre for Biomedical Education (INMEBE)
Journal or Publication Title: Journal of Pharmacology and Experimental Therapeutics
ISSN: 0022-3565
Dates:
DateEvent
1 September 2005Published
PubMed ID: 15923343
Web of Science ID: 15923343
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/100961
Publisher's version: https://doi.org/10.1124/jpet.105.086272

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